This invention relates to (+) 1-methyl-4-(3-cyano-5H-dibenzo[a,d]-cyclohepten-5-ylidene)piperidine (hereinafter referred to as "(+) 3-cyanocyproheptadine") having pharmaceutical utility as a peripheral and central anticholinergic agent; and to (-) 1-methyl-4-(3-cyano-5H-dibenzo[a,d]-cyclohepten-5-ylidene)piperidine (hereinafter referred to as "(-) 3-cyanocyproheptadine") having pharmaceutical utility as a major tranquilizer. Further this invention relates to a process for resolving racemic 3-cyanocyproheptadine into (-) 3-cyanocyproheptadine and (+) 3-cyanocyproheptadine; to pharmaceutical compositions comprising either isomer substantially free of the other; pharmaceutical compositions comprising preferred ratios of the (+) and (-) isomers; and to methods of treatment comprising administering such compounds and compositions.
The symbols, "(+)" and "(-)," as used above, indicate that under the conditions of measurement hereinafter described, e.g., frequency, temperature and solvent, the subject compounds rotate the plane of polarized light to the right or left, respectively, when viewed according to the established convention. For purposes of this invention the phrase "substantially free" when referring to the state of purity of one isomer with respect to its enantiomer is defined to be a contamination of the pure isomer by from about 0.1 to about 5.0 wt. % of its enantiomer.
The racemic 3-cyanocyproheptadine (structure I, below) has been disclosed in commonly assigned, copending U.S. Pat. application Ser. No. 476,630, filed June, 5, 1974 of John D. Prugh, now U.S. Pat. No. 3,988,342, which application is a continuation-in-part of Ser. No. 280,685, filed Aug. 14, 1972, now U.S. Pat. No. 3,960,872, which in turn is a continuation-in-part of U.S. Ser. No. 9,049, filed Feb. 5, 1970, now abandoned, which in turn is a continuation-in-part of U.S. Ser. No. 4,123, filed Jan. 19, 1970, now abandoned. For the purpose of describing the synthesis of the racemic 3-cyanocyproheptadine, such applications are incorporated herein by reference. ##STR1##
However, there is no disclosure in the above-mentioned U.S. patent applications that resolution of the racemic 3-cyanocyproheptadine also effects a separation of pharmacological activity. Thus while the racemic 3-cyanocyproheptadine is a potent major tranquilizer it also has potent anticholinergic activity which latter activity can give rise to undesired side effects; the (+) isomer, however, has no tranquilizing activity but is a potent peripheral and central anticholinergic agent and can be used as an anticholinergic agent or for treatment of the extrapyramidal effects of haloperidol and similar agents; whereas the (-) isomer has no central or peripheral anticholinergic activity but is a major tranquilizer. The unexpected separation of pharmacological activity by optical resolution of the racemic 3-cyanocyproheptadine into its enantiomer is of significant value since it is now possible to obtain either tranquilizing effects, anticholinergic effects or a desired combination of such effects by administering either isomer substantially free of its enantiomer or by administering a combination of the isomers in preferred ratios.
Thus it is an object of the present invention to provide (+) 3-cyanocyproheptadine substantially free of the corresponding (-) enantiomer; (-) 3-cyanocyproheptadine substantially free of the corresponding (+) enantiomer; and preferred ratios of the two isomers. It is also an object of the present invention to provide processes for the preparation (resolution) of such optical isomers from the racemic mixture.
A further object of this invention is to provide pharmaceutical compositions comprising therapeutically effective amounts of such isomers substantially free of the corresponding enantiomer and compositions comprising therapeutically effective amounts of preferred blends of such isomers. Further it is an object of the present invention to provide methods of treatment comprising administering such compounds and compositions when the effects of a major tranquilizer, anticholinergic agent, or a combination of said effects is indicated.
Lastly, it is an object of the present invention to provide pharmaceutically acceptable acid addition salts of the above-described compounds.